Aromatic amides and carbomates of phenylamidines

ABSTRACT

N-Phenylacetamidines bearing an acylamino group in the phenyl ring have anthelmintic activity and are effective against nematodes and cestodes. A representative embodiment is N-(4-carbophenoxyaminophenyl)-N&#39; ,N&#39;-dimethylacetamidine.

This is a division of application Ser. No. 398,692 filed Sept. 19, 1973,which in turn is a division of Ser. No. 151,581 filed June 9, 1971, nowU.S. Pat. No. 3,818,070.

The present invention relates to new aminophenylamidines, to processesfor their production, and to their pharmaceutical use. These newcompounds are useful as paraciticides, especially as anthelmintics.

Some acylaminophenylformamidines, such asN-(p-acetamidophenyl)-N',N'-dimethylformamidine (U.S. Pat. No.3,184,482) and N-phenyl-acetamidines, such asN-(p-chlorophenyl)-N',N'-dimethylacetamidine, are already known. Thesecompounds are however inactive against the helminths mentioned below.

This invention provides aminophenylamidines of the general formula:##STR1## in which R is a straight, cyclic, of 3 to 7 carbon atoms orbranched-chain alkyl, alkenyl or alkoxy group;

R² is a --COR⁶ group or an --SO₂ R⁷ group in which R⁶ is a hydrogenatom; a straight-or branched-chain alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyloxy or alkoxyalkyl group; a cycloakylgroup or a cycloalkenyl group containing one or two double bonds, whichcycloalkyl and cycloalkenyl groups can be substituted by one or morealkyl groups; a cycloalkylalkyl, benzocycloalkylalkyl, tetrahydrofuryl,tetrahydrofurfuryl or tetrahydropyranyl group which can be substitutedby one or more alkyl groups; a trifluoromethyl group; an alkyl groupsubstituted by one or more halogen atoms or by one or more cyano,hydroxy, acyloxy, alkoxy or oxo-groups; a carbalkoxy- alkyl group; acycloalkyl-alkoxy group; a cycloalkoxy- or tetrahydrofurylalkoxy group;a phenylalkoxy, phenoxyalkoxy, phenoxy, phenylalkyl, phenyl,phenylalkenyl or naphthyl group, in which the aromatic ring can besubstituted by one or more alkyl, alkenyl, alkoxy, hydroxy, acyloxy,nitro, trifluoromethyl, cyano, carbethoxy, alkylsulphonyl, acylamino oralkylsulphonyl-amino groups or fluorine, chlorine or bromine atoms; ahetero-aromatic ring system which can be substituted by one or morealkyl groups; a furylalkyl, thienylalkyl, indolylalkyl, furylalkoxy orthienylalkoxy, group which can be substituted by one or more alkylgroups; or a phenylalkyl group, the alkyl part of which is substitutedby a hydroxy, acyloxy, or alkoxy group; and

R⁷ is a straight- or branched-chain alkyl or alkenyl group, an aralkylgroup, a cycloalkyl group, or a cycloalkyl-alkyl group;

R³, r⁸ and R⁹ be the same or different and is each a hydrogen or halogenatom or a straight- or branched-chain alkyl, alkenyl or alkoxy group ora cyano or trifluoromethyl group;

R⁴ is a straight- or branched-chain alkyl, alkenyl, alkynyl or alkoxygroup; and

R⁵ is a straight- or branched-chain alkyl or alkenyl group or acyclo-alkyl group; and their salts.

These compounds are useful for combating parasites, especiallyhelminths.

The alkyl groups R as well as the alkyl part of the alkoxy groups R,preferably contain 1 to 5, especially 1 or 2, carbon atoms, and thealkenyl group R preferably contains 2 to 5 carbon atoms.

The cycloalkyl group R⁵ preferably contains 3 to 7, more preferably 5 to7, carbon atoms.

The alkyl groups, and the alkyl component of the alkoxy groups R³, R⁸and R⁹ preferably contain 1 to 4, especially 1 or 2, carbon atoms. Thealkenyl groups R³, R⁸ and R⁹ preferably contain 2 to 4 carbon atoms.

Halogens R³, R⁸ and R⁹ are generally fluorine, chlorine and bromine, butpreferably chlorine.

Alkyl radicals, as well as the alkyl constituents of the alkoxy groupsR⁴, preferably contain 1 to 4, especially 1 or 2, carbon atoms. Alkenyland alkynyl radicals R⁴ preferably contain 2 to 4 carbon atoms.

Alkyl R⁵ preferably contain 1 to 5, especially 1 or 2, carbon atoms, andalkenyl groups R⁵ preferably contain 2 to 5 carbon atoms.

The alkyl groups, and the alkyl component of the alkoxy groups R⁶,preferably contain 1 to 6, especially 1 to 3, carbon atoms. The alkenyland alkynyl groups R⁶, and the alkenyl and alkynyl components of thealkenyloxy and alkynyloxy groups R⁶, preferably contain 2 to 6,especially 2 or 3, carbon atoms. Alkoxyalkyloxy and alkoxyalkyl groupsR⁶ preferably each contain 2 to 6, preferably 2 or 3, carbon atoms.Cycloalkyl groups R⁶ contain 3 to 7, preferably 3 to 6, carbon atoms.The cycloalkyl groups R⁶ can contain one or more, preferably one, alkylgroup having preferably 1 to 4, especially 1 or 2, atoms.

The cycloalkylalkyl groups R⁶ generally contain 3 to 7, preferably 5 to6, carbon atoms in the cycloalkyl part, and preferably 1 to 4,especially 1 or 2, carbon atoms in the alkyl part. Thebenzoylcycloalkylalkyl groups R⁶ preferably contain 1 to 4, especially 1or 2, carbon atoms in each alkyl part.

The cycloalkylalkyl, benzocycloalkylalkyl and tetrahydrofuryl,tetrahydrofurfuryl and tetrahydropyranyl groups R⁶ can be substituted byone or more alkyl groups with, preferably, 1 to 4, especially 1 or 2,carbon atoms. The alkyl groups R⁶ substituted by one or more, preferably1, halogen atom, especially fluorine, chlorine or bromine, or by one ormore, especially one, nitrile, hydroxyl or oxo group, preferably contain1 to 4, especially 1 or 2, carbon atoms. The carbalkoxyalkyl groups R⁶generally contain 1 to 4, preferably 1 or 2, carbon atoms in the alkylpart. The cycloalkylalkoxy groups R⁶ generally contain 3 to 7,preferably 5 or 6, carbon atoms in the cycloalkyl part and 1 to 4,preferably 1 or 2, carbon atoms in the alkyl or alkoxy component. Thecycloalkoxy groups R⁶ generally contain 3 to 7, preferably 5 or 6,carbon atoms. The alkyl or alkoxy components of thetetrahydrofurylalkoxy group, phenylalkoxy group, phenoxyalkoxy group andphenylalkyl group mentioned under R⁶ preferably contain 1 to 4,especially 1 or 2, carbon atoms. The phenylalkenyl groups R⁶ preferablycontain 2 to 4 carbon atoms in the alkenyl part.

If R⁶ represents an aromatic radical (phenyl or naphthyl), or if theradicals R⁶ contain aromatic constituents (phenyl or naphthyl), thearomatic structures can contain one or more, preferably 1 or 2,substituents. Possible substituents are alkyl radicals with 1 to 4,preferably 1 or 2, carbon atoms, alkenyl radicals with 2 to 4 carbonatoms, alkoxy radicals with 1 to 4, preferably 1 or 2, carbon atoms,acyloxy radicals with 2 to 4, preferably 2 or 3, carbon atoms,alkylsulphonyl radicals with 1 to 4, preferably 1 or 2, carbon atoms,acylamino radicals with 2 to 4, preferably 2, carbon atoms, andalkylsulphonylamino radicals with 1 to 4, preferably 1 or 2, carbonatoms.

The hetero-aromatic O-, S- or N-containing ring system R⁶ generallycomprises a 5- or 6-membered hetero-aromatic ring, which can contain 1to 3, preferably 1 or 2, hetero-atoms, such as oxygen, sulphur andnitrogen; a benzene ring can be fused to the hetero-aromatic ring. Thehetero-aromatic ring system can be substituted by one or more,preferably 1 or 2, alkyl groups with 1 to 4, preferably 1 or 2, carbonatoms, The furyl, thienyl, isoxazolyl, pyrimidinyl, imidazolyl,pyrazolyl, indolyl, thianaphthyl, quinolyl, phenothiazinyl, thiadiazolyland thiazolyl groups may be mentioned as examples.

Furylalkyl, thienylalkyl, indolylalkyl, furylalkyloxy andthienylalkyloxy groups R⁶ generally possess 1 to 4, preferably 1 or 2,carbon atoms in the alkyl or alkoxy component. The hetero-aromaticconstituents can be substituted by one or more, preferably 1 or 2, alkylgroups with 1 to 4, preferably 1 or 2, carbon atoms.

Alkyl groups R⁷ preferably contain 1 to 6, especially 1 or 2, carbonatoms, and alkenyl groups R⁷ preferably contain 2 to 6 carbon atoms.

Aralkyl groups R⁷ generally contain 6 or 10 carbon atoms in the arylpart and 1 to 4, preferably 1 or 2, carbon atoms in the alkyl part.

The cycloalkyl groups, as well as the cycloalkyl constituent of thecycloalkyl-alkyl group R⁷, generally contain 3 to 7, preferably 5 or 6,ring members. The cycloalkyl-alkyl group R⁷ generally possesses 1 to 4,preferably 1 or 2, carbon atoms in the alkyl part.

The aminophenylamidines according to the invention are basic incharacter. They can be used as free bases or in the form of their salts,for example hydrohalides, preferably hydrochlorides, sulphates,phosphates, nitrates, acetates or naphthalenedisulphonates.

Particularly preferred compounds are those of the general formula:##STR2## in which R is a methyl or ethyl group;

R² is a --COR⁶ group or an --SO₂ R⁷ group, in which R⁶ is a hydrogenatom, a straight- or branched-chain alkyl or alkenyl group containing upto 3 carbon atoms and optionally substituted by a trifluoromethyl ormethoxy group; a cycloalkyl group with 3 to 5 carbon atoms; a furylgroup; a 5-methylisoxazolyl group; a phenyl group; or an alkoxy oralkynyloxy group containing up to 4 carbon atoms and optionallysubstituted by a methoxy group; and R⁷ is a methyl or ethyl group;

R³ is a hydrogen or chlorine atom;

R⁵ is a hydrogen atom or a methyl or ethyl group;

R⁴ is a methyl, ethyl or methoxy group; and their physiologicallytolerated salts.

Preferred salts of the new compounds are the hydrochlorides.

The invention also provides a number of processes designated as (a),(b), (c), (d), (e) and (f) for the production of the newaminophenylamidines and salts.

In process (a), an aniline derivative of the general formula: ##STR3##is reacted with a carboxylic acid amide or thioamide of the generalformula: ##STR4## in which general formula W is oxygen or sulphur and Rto R⁵, R⁸ and R⁹ are as defined above, or with a salt or reactivederivative thereof. The reaction may be carried out in the presence of acondensation agent and optionally of an inert solvent. The reactionproducts may be isolated in the form of a salt or in the form of thefree base and then converted if necessary into any other desired salt inany suitable manner.

As reactive derivatives there may be used, for example, compoundsobtained by reaction of an amide or thioamide of the general formula (4)with an organic acid (for example, hydrochloric acid, boron trichlorideor sulphuric acid), with an inorganic or organic acid halide (forexample, phosphorus oxychloride, phosphorus pentachloride, phosgene,thionyl chloride, benzoyl bromide, p-toluenesulphonyl chloride or amixture of phosgene/aluminum chloride or phosgene/hydrogen chloride orphosgene, or phosphorus oxychloride), with a trialkyloxonium fluoboratehaving 1 to 5 carbon atoms per alkyl group, with a dialkyl sulphatehaving 1 to 5 carbon atoms per alkyl group, or with an alkyl halidehaving 1 to 5 carbon atoms.

Further reactive amide derivatives that may be used are acetals andthioacetals of the general formula: ##STR5## in which W, R, R⁴ and R⁵are as defined above and "Alkyl" denotes an alkyl group having up to 4carbon atoms.

As examples of condensation agents which can be employed in process (a),there may be mentioned: inorganic acids (for example, hydrochloric acid,boron trichloride or sulphuric acid); inorganic or organic acid halides(for example, phosphorus oxychloride, phosphorus pentachloride,phosgene, thionyl chloride, benzoyl bromide, p-toluenesulphonyl chlorideor a mixture of phosgene/aluminum chloride or phosgene/hydrogen chlorideor phosgene, phosphorus oxychloride); trialkyloxonium fluoborates, (1 to5 carbon atoms per alkyl group); dialkyl sulphates (1 to 5 carbon atomsper alkyl group); and alkyl halides (1 to 5 carbon atoms).

In the case of the reaction of thioamides (general formula (4);W=sulphur), a desulphurising agent, for example, HgO, Ag₂ O or Hg(CN)₂,can advantageously be used additionally to these condensation agents, orwithout these condensation agents.

The reactants are preferably employed in the stoichiometrically requiredamounts.

As solvents, it is possible to use any inert organic solvents; theseinclude aromatic, optionally halogenated, hydrocarbons, for example,benzene, toluene and dichlorobenzene; optionally chlorinated aliphatichydrocarbons for example, methylene chloride and chloroform;tetramethylenesulphone, and lower aliphatic alcohols; for example,methanol and ethanol.

The reactants are preferably brought together at room temperature (about20° C) and can be warmed to between 30° and 150° C, preferably 70° to120°, in order to complete the reaction.

The success of the reaction does not depend on the sequence in which thereactants are brought together. The new compounds are isolated in theusual manner.

Process (b) comprises reacting an amine of the general formula: ##STR6##with an anilide of the general formula: ##STR7## in which generalformulae W, R to R⁵, R⁸ and R⁹ are as defined above, or with a salt or areactive derivative thereof.

The reaction is optionally carried out in the presence of a solvent andoptionally in the presence of a condensation agent.

Reactive anilide derivatives suitable for use in process (b) are, forexample, those obtained by the reaction of an anilide of general formula(7) with an inorganic acid (such as hydrogen chloride, boron trichlorideor sulphuric acid), with an inorganic or organic acid halide (such asphosphorus oxychloride, phosphorus pentachloride, phosgene, thionylchloride, benzoyl bromide, p-toluenesulphonyl chloride or a mixture ofphosgene/aluminum chloride, or phosgene/hydrogen chloride or phosgene,phosphorus oxychloride), with a trialkyloxonium fluoborates having up to1 to 5 carbon atoms in each alkyl group, with a dialkyl sulphate havingup to 5 atoms in each alkyl group or with an alkyl halide having up to 5carbon atoms.

Other reactive anilide derivatives suitable for use in process (b) areacetals and thioacetals of the general formula: ##STR8## in which R, R¹,R², R³, R⁸, R⁹ and W are as defined above, Alkyl denotes an alkyl grouphaving up to 4 carbon atoms, and the two alkyl groups together can forma 5- or 6- or 7-membered ring.

Further reactive anilide derivatives suitable for use in process (b) areiminoethers of the general formula: ##STR9## in which R, R¹, R², R³, R⁸,R⁹ and W are as defined above and Alkyl denotes an alkyl group having upto 4 carbon atoms.

Process (b) is carried out under the same reaction conditions (molarratio, temperature, condensation agent and solvent) as process (a).

Process (c) comprises heating an arylisocyanate of the general formula:##STR10## with an amide or thioamide of the general formula: ##STR11##in which general formulae W, R to R⁵, R⁸ and R⁹ are as defined above.

The progress of the reaction can be followed from the accompanyingevolution of CO₂ or COS.

Process (d) comprises heating a compound of the general formula:##STR12## with an amide or thioamide of the general formula: ##STR13##in which general formulae R to R⁵, R⁸, R⁹ and W are as defined above.

In the processes (c) and (d), the reactants are preferably reacted inmolar ratios.

The reactions are expediently carried out at temperatures between 80°and 200° C, preferably between 110° and 180° C, optionally in thepresence of an inert organic solvent.

As examples of such solvents suitable for use in process (c) or (d)there may be mentioned benzene, toluene and dichlorobenzene.

Process (e) is applicable to those aminophenylamidines of the inventionin which R⁴ and R⁵ are alkyl or alkenyl groups, and comprises reacting aphenylamidine of the general formula: ##STR14## with an alkylating agentof the general formula:

    B -- R.sup.10                                              ( 14)

in which general formulae R, R², R³, R⁸ and R⁹ are as defined above, R¹⁰is a straight- or branched-chain alkyl or alkenyl group, and B is areactive ester group or a halogen atom.

Preferred halogen atoms B are chlorine, bromine and iodine. Preferredreactive ester groups are arylsulphonyloxy and alkylsulphonyloxy groups,for example, methanesulphonyloxy and toluenesulphonyloxy groups.

The compounds of the general formula (13) can, for example, be obtainedin a known manner by the reaction of an aniline derivative of generalformula (3) with a nitrile of the general formula:

    R -- CN                                                    (15)

in which R is as defined above, optionally in the presence of acondensation agent for example, aluminum chloride.

The reactants in process (e) are preferably employed in molar amounts.The reaction takes place at temperatures between 0° and 120° C, and ispreferably carried out at 20° to 80° C, in the presence of an inertorganic solvent.

Ethers, for example, diethyl ether or tetrahydrofurane and alkylnitrilesfor example, acetonitrile are, for example, suitable as solvents. Itcan, at times, also be desirable to add an acid-binding agent, forexample, an alkali metal carbonate or an alkaline earth metal carbonate,preferably sodium or potassium carbonate.

Finally, process (f) comprises reacting an aminophenylamidine of thegeneral formula: ##STR15## with an acylating or sulphonylating agent ofthe general formula:

    Y -- Z                                                     (17)

in which general formulae R, R⁴, R⁵, R⁸ and R⁹ are as defined above, Zis a group --COR⁶ or --SO₂ R⁷, in which R⁶ and R⁷ are as defined above,and Y is a reactive acid group or a halogen atom optionally in thepresence of a solvent and optionally in the presence of an acid-bindingagent.

Halogen atoms Y are preferably chlorine and bromine atoms. When Z is a--COR⁶ group, Y is a --O--CO--R⁶ _(") or --OR⁶ _(") ^(') group in whichR⁶ _(") and R⁶ _(") ^(') are as defined above for R⁶ and can be the sameor different to R⁶ in the acylating or sulphonylating agent of generalformula (17).

If Z is an --SO₂ R⁷ group, Y is a halogen atom.

As the alkylating or sulphonylating agent Y-Z, there may especially bementioned: lower alkylpyrocarbonic acid esters with 1 to 4 carbon atomsin the alkyl part; lower chloroformic acid alkyl esters with,preferably, 1 to 4 carbon atoms in the alkyl component; loweralkylcarboxylic acid chlorides and bromides with, preferably, 1 to 4carbon atoms in the alkyl group; formic acid alkyl esters with 1 to 4carbon atoms in the ester part; methanesulphonic acid chloride; benzoylchloride and acetic anhydride; or mixed anhydrides, such asformic-acetic anhydride.

In process (f), the reactants are preferably brought together in molaramounts.

The reaction temperatures are expediently 0° to 120° C, preferably 20°to 90° C.

As solvents, it is possible to employ any solvent that is inert duringthis reaction. Lower aliphatic alcohols for example, methanol or ethanolaromatic hydrocarbons for example, benzene and toluene, petroleum ether,chlorinated hydrocarbons for example, chloroform and methylene chloride,as well as tetramethylenesulphone, may be mentioned as examples.

The aminophenylamidines (16) can for example be obtained from thenitrophenylamidines and/or their salts, of the general formula:##STR16## in which R, R³ , R⁴, R⁵, R⁸ and R⁹ are as defined above byreduction, in any suitable manner.

The starting compounds required for the production of the new compoundsare known or are obtainable by processes known in the art.

The following may be mentioned as examples of the starting material: 2-,3- or 4-carbethoxyamino-aniline; carbomethoxyamino-aniline;carbisopropoxyamino-aniline; carbutoxyamino-aniline;methylsulphonylamino-aniline; ethylsulphonylamino-aniline;acetamino-aniline; propionylaminoaniline; butyrylamino-aniline;isovaleroyamino-aniline; formylamino-aniline;dimethylsulphamoyl-aniline; acryloylamino-aniline;methacryloylamino-aniline; crotonylaminoaniline;methoxypropionyl-aniline; ethoxyacetylamino-aniline;methoxyacetylamino-aniline; carballyloxyamino-2-chloroaniline;4-carbethoxyamino-3-chloro-5-methyl-aniline;4-carbethoxy-amino-3,5-dimethylaniline;4-(N-carbethoxy-N-methyl-amino)-aniline;4-carbethoxyamino-3-bromoaniline;4-carbethoxyamino-trifluoromethylaniline;2,5-dichloro-4-acetamino-aniline;2,5-dichloro-4-carbethoxyamino-aniline;3,5-dichloro-4-carbethoxyaniline; 2-chloro-4-carbethoxy-5-methylaniline;5-chloro-4-carbethoxy-2-methyl-aniline and2,4-dimethyl-5-carbethoxyamino-aniline; N-(4-nitrophenyl)-N',N'-dimethyl-acetamidine; N-(4-nitrophenyl)-N',N'-diethylacetamidine;N-(4-nitrophenyl)-N',N'-dimethylpropionamidine;N-(4-nitrophenyl)-N',N'-diethylpropionamidine andN-(4-nitrophenyl)-N'-ethyl-N'-methyl-acetamidine.

The salts of the aminophenylamidines according to the invention can beobtained from the free bases in the usual manner.

The production of the new compounds by processes according to theinvention is illustrated in the Examples which follow.

All temperatures are given in °C.

EXAMPLE 1 ##STR17##

4-Carbethoxyamino-aniline and 46.6 g of N,N-dimethylacetamide aredissolved in 1000 ml of toluene. 79.5 g of phosphorus oxychloride areadded dropwise thereto at 20°, and the mixture is stirred for 90 minutesat 20° and heated for 4 hours under reflux. After decanting off thetoluene, the residue is taken up in a mixture of water and chloroform,sodium hydroxide solution is added whilst cooling, inorganic productsare filtered off, and the organic phase is separated off. Afterevaporating the organic phase, 101 g of crudeN-(4-carbethoxyaminophenyl)-N',N'-dimethyl-acetamidine are obtained;this is recrystallised from ethyl acetate. Melting point 130° - 131°,yield 84 g. The hydrochloride is obtained by dissolving the compound inether and adding a solution of hydrochloric acid in ether, and isrecrystallised from a mixture of ethyl acetate and alcohol. Meltingpoint 222° (decomposition). The same compound is also obtained ifphosgene or p-toluenesulphonyl chloride are used as condensation agents.

The following compounds are prepared by proceeding analogously:N-(4-carbomethoxyaminophenyl)-N',N'-dimethylacetamidine, melting point137° - 139°;

N-(4-carbethoxyaminophenyl)-N',N' -dimethylpropionamidine, melting point114° - 115°;

N-(4-carbethoxyaminophenyl)-N',N'-dimethyl-butyramidine;

N-(4-carbethoxyaminophenyl)-N',N'-diethyl-isobutyramidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethyl-pivalylamidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethyl-valeramidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethyl-acrylamidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethyl-crotylamidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethyl-β,β-dimethylacrylamidine;

N-(4-carbethoxyaminophenyl)-N',N'dimethyl-α-methacrylamidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethy-α-methoxyacetamidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethyl-ethoxyacetamidine;

N-(4-carbethoxyaminophenyl)-N',N' -dimethyl-cyclopropylcarboxamidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethylcyclobutylcarboxamidine;

N(4-carbethoxyaminophenyl)-N',N'-dimethyl-cyclopentylcarboxamidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethyl-cyclohexylcarboxamidine;

N-(4-carbethoxyaminophenyl)-N',N'-diethylacetamidine; melting point88° - 90°;

N-(4-carbethoxyaminophenyl)-N'-ethyl-N-methyl-acetamidine, melting point105° - 107°; hydrochloride, melting point 195° - 196°;

N-(4-carbethoxyaminophenyl)-N'-methyl-N'-propyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-ethyl-N'-propyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-methyl-N'-isopropyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-allyl-N'-methyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-crotyl-N'-methyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-methallyl-N'-methyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-methyl-N'-(β-methyl-vinyl)-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-methyl-N'(β,β-dimethyl-vinyl)-acetamidine;

N-(4-carbethoxyaminophenyl)-N',N'-diallyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N',N'-dicrotyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-methyl-N'-propynyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-methyl-N'-cyclopentylacetamidine;

N-(4-carbethoxyaminophenyl)-N'-methyl-N'-cyclohexyl-acetamidine; and

N-(4-carbethoxyaminophenyl)-N'-methyl-N'-cycloheptylacetamidine.

EXAMPLE 2

15.3 g of pyrocarbonic acid ethyl ester are added dropwise to 17.7 g ofN-(4-aminophenyl)-N',N'-dimethylacetamidine (melting point 92° - 93°)dissolved in 200 ml of tetrahydrofurane, the mixture is heated to 50°for one hour and evaporated in vacuo, and theN-(4-carbethoxyaminophenyl)-N',N'-dimethyl-acetamidine, described inExample 1, is recrystallised from ethyl acetate. Melting point 130° -131°.

The N-(4-aminophenyl)-N',N'-dimethylacetamidine used as the startingmaterial is obtained by catalytic hydrogenation ofN-(4-nitrophenyl)-N',N'-dimethyl-acetamidine (melting point 94° - 95°),or of its hydrochloride, with Raney nickel as the catalyst.

EXAMPLE 3 ##STR18##

13.7 g of chloroformic acid n-butyl ester are added dropwise, at 20°, to17.7 g of N-(4-aminophenyl)-N,N-dimethyl-acetamidine, dissolved in 150ml of ethanol, and the mixture is heated for one hour under reflux andevaporated in vacuo. After recrystallisation from ethanol/ethyl acetate,25.5 g of pure N-(4-carbobutoxy-aminophenyl)-N',N'-dimethylacetamidinehydrochloride, melting point 210° - 212° (decomposition), are obtained.

The following are obtained by analogous processes:

N-(4-carboisopropoxyaminophenyl)-N,N'-dimethyl-acetamidinehydrochloride, melting point 232° - 235°;

N-(4-carbopropoxyaminophenyl)-N',N'-dimethyl-acetamidine hydrochloride,melting point 205° - 206°;

N-(4-carboisobutoxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carballyoxyaminophenyl-N',N'-dimethyl-acetamidine hydrochloride;

N-(4-carbocrotyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbomethallyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbopropynyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride; melting point,(crude) 205°- 207°; the free base, meltingpoint 126° - 128° is obtained therefrom by adding sodium hydroxidesolution;

N-[4-carbo-(3,3-dimethylhexyloxy)aminophenyl]-N',N'-dimethylacetamidine,melting point 128°;

N[4-carbo-(β-methoxyethyloxy)-aminophenyl]-N',N'-dimethylacetamidinehydrochloride, melting point 189° - 191° (decomposition); free base;melting point 126° - 128°;

N-(4-carbocyclopropyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N(4-carbocyclobutyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbocyclopentyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbocyclohexyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbocyclohexylmethyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbobenzoxyaminophenyl)-N',N'-dimethyl-acetamidine hydrochloride;

N-(4-carbophenethyloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbotetrahydrofuryloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbotetrahydrofurfuryloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbofurfuryloxyaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbothienyl(2)-methoxy-aminophenyl)-N',N'-dimethyl-acetamidinehydrochloride;

N-(4-carbophenoxy-aminophenyl)-N',N'-dimethyl-acetamidine hydrochloride,melting point 233° - 235°; and

N[4-carbo-(4-chlorophenoxy)-aminophenyl]-N',N'-dimethyl-acetamidinehydrochloride, melting point 236° - 238°.

EXAMPLE 4 ##STR19##

Following the method described in Example 1, reaction of4-aminoacetanilide and dimethylacetamide in the presence of phosphorusoxychloride as the condensation agent yieldsN-(4-acetyl-aminophenyl-N',N'-dimethylacetamidine, melting point 132° -134°, in a yield of 93% of theory; hydrochloride, melting point 258° -260°.

The following are obtained by analogous processes:

N-(4-acetaminophenyl)-N',N'-dimethyl-propionamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-butyramidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-isobutyramidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-valeramidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-pivalylamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-acrylamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-crotylamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-methallylamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-β,β-dimethylacrylamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-methoxyacetamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-ethoxyacetamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-cyclopropylcarboxamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-cyclobutyl-carboxamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-cyclopentyl-carboxamidine;

N-(4-acetaminophenyl)-N',N'-dimethyl-cyclohexyl-carboxamidine;

N-(4-acetaminophenyl)-N',N'-diethyl-acetamidine;

N-(4-acetaminophenyl)-N'-ethyl-N'-methyl-acetamidine;

N-(4-propionylaminophenyl)-N'-ethyl-N'-methyl-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-propyl-acetamidine;

N-(4-acetaminophenyl)-N-ethyl-N'-propyl-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-isopropyl-acetamidine;

N-(4-acetaminophenyl)-N'-allyl-N'-methyl-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-(β,β-dimethyl-vinyl)-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-cyclopentyl-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-cyclohexyl-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-cyclohexyl-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-cycloheptyl-acetamidine;

N-(4-cyclopentylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine,hydrochloride, melting point 244° - 247°;

N-(4-cyclohexylmethylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-phenylacetylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-phenethylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-[4-tetrahydrofurfurylcarbonyl-(2)-aminophenyl]-N',N'-dimethyl-acetamidine;

N-[4-(5-methyltetrahydrofuryl-carbonyl-[2]-aminophenyl]-N',N'-dimethyl-acetamidine;

N-[4-(2-methyl-tetrahydrofuryl-carbonyl-[2]-aminophenyl]-N',N'-dimethyl-acetamidine;

N-[4-tetrahydrofurfuryl-carbonyl-(2)-aminophenyl]-N',N'-dimethyl-acetamidine;

N-[4-tetrahydropyranyl-carbonyl-aminophenyl]-N',N'-dimethyl-acetamidine;

N-(4-trifluoro-acetylaminophenyl)-N',N'-dimethyl-acetamidine,hydrochloride, melting point 273° - 274°;

N-(4-trichloro-acetylaminophenyl)-N',N'-dimethyl-acetamidine;

N-[4-(β,β,β-trichloropropionyl)-aminophenyl]-N',N'-dimethyl-acetamidine;

N-(4-carbethoxy-carbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-carbethoxymethylene-carbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-β-carbethoxyethylene)-carbonylaminophenyl-N',N'-dimethyl-acetamidine;

N-(4-cyanomethylenecarbonylaminophenyl)-N',N'-dimethyl-acetamidine.

EXAMPLE 5 ##STR20##

18.5 g of propionyl chloride are added dropwise to a solution of 35.4 gof N-(4-aminophenyl)-N',N'-dimethyl-acetamidine in 300 ml of toluene.The mixture was stirred for a further hour, and after evaporation andrecrystallisation from ethanol/ethyl acetate, 43.5 g ofN-(4-propionylaminophenyl)-N',N'-dimethyl-acetamidine hydrochloride,melting point 257° - 258°, are obtained. The free base is obtainedtherefrom by adding sodium hydroxide solution.

The following are obtained by analogous processes:

N-(4-butyrylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-isobutyrylaminophenyl)-N',N'-dimethyl-acetamidine, hydrochloride,melting point 248° - 250°;

N-(4-pivaloylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-valeroylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(acryloylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(crotonoylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(methacryloylaminophenyl)-N',N'-dimethyl-acetamidine, hydrochloride,melting point 216°-218°;

N-propynylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(methoxyacetylaminophenyl)-N',N'-dimethyl-acetamidine, hydrochloride,melting point 205°- 207° (decomposition);

N-(cyclopropylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine,hydrochloride, melting point 282° - 284°;

N-(cyclobutylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(cyclopentylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;hydrochloride, melting point 244°-247°;

N-(cyclohexylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(cycloheptylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(methylcyclopentylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(methyl-cyclohexylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(cyclopentenylcarbonylaminophenyl)-N',N'-dimethyl-acetamidine; and

N-(cyclohexenyl-1-carbonylaminophenyl)-N',N'-dimethyl-acetamidinehydrochloride, melting point 264°-268° (decomposition).

EXAMPLE 6 ##STR21##

Following the method described in Example 1, 90 g of4-carbethoxyamino-3-chloro-aniline, 46.6 g of N,N-dimethyl-acetamide and79.5 g of phosphorus oxychloride in 100 ml of toluene yield 37 g ofN-(4-carbethoxy-amino-3-chlorophenyl)-N',N'-dimethyl-acetamidine,melting point 73° - 74°.

The following compounds are obtained by analogous processes:

    ______________________________________                                         ##STR22##                   (24)                                             R.sup.I    R.sup.II                                                                             R.sup.III                                                                            R.sup.IV   Melting point                             ______________________________________                                        2-Cl       CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5 C.sub.2 OOC                                                                    HCl 212°                           2,5-Cl.sub.2                                                                             CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5 C.sub.2 OOC                                                                    decomposition                             2-CH.sub.3 CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5 C.sub.2 OOC                                3-CH.sub.3 CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5 C.sub.2 OOC                                2,6-(CH.sub.3).sub.2                                                                     CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5 C.sub.2 OOC                                3-C.sub.2 H.sub.5                                                                        CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5 C.sub.2 OOC                                3-CHCHCH.sub.2                                                                           CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5 C2OOC                                      3-F        CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5 C.sub.2 OOC                                2-Cl       CH.sub.3                                                                             CH.sub.3                                                                             4-CH.sub.3CO                                                                             HCl 172-174°                       3-Cl       CH.sub.3                                                                             CH.sub.3                                                                             4-CH.sub.3CO                                                                             decomposition                             3-OCH.sub.3                                                                              CH.sub.3                                                                             CH.sub.3                                                                             4-CH.sub.3CO                                         3-Br       CH.sub.3                                                                             CH.sub.3                                                                             4-CH.sub.3CO                                         3-CF.sub.3 CH.sub. 3                                                                            CH.sub.3                                                                             4-CH.sub.3CO                                         2-Cl       CH.sub.3                                                                             CH.sub.3                                                                              ##STR23## HCl 252-253° decomposition         3-CN       CH.sub.3                                                                             CH.sub.3                                                                             4-CH.sub.3CO                                         3-Cl       CH.sub.3                                                                             CH.sub.3                                                                             4-C.sub.2 H.sub.5CO                                  2-Cl       CH.sub.3                                                                             CH.sub.3                                                                             4-C.sub.2 H.sub.5CO                                  2-Cl       CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      4-CH.sub.3CO                                         3-Cl       CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      4-CH.sub.3CO                                         2-Cl       CH.sub.3                                                                             CH.sub.3                                                                             4-C.sub.6 H.sub.5CO                                                                      HCl 290°                           2-CF.sub.3 CH.sub.3                                                                             CH.sub.3                                                                             4-H.sub.5C.sub.2 OOC                                 2-CF.sub.3 CH.sub.3                                                                             CH.sub.3                                                                             4-CH.sub.3CO                                         ______________________________________                                    

EXAMPLE 7 ##STR24##

10.7 g of methanesulphonic acid chloride are added dropwise to 16.8 g ofN-(4-aminophenyl)-N',N'-dimethyl-acetamidine in 300 ml of toluene, themixture is stirred for a further hour, and the hydrochloride which hasprecipitated is filtered off and recrystallised from ethanol. 15.8 g ofN-(4-methylsulphonyl-aminophenyl)-N',N'-dimethyl-acetamidinehydrochloride. melting point 273°. are obtained.

The following compounds are obtained by analogous processes:

N-(4-ethylsulphonylaminophenyl)-N'-N'-dimethyl-acetamidine,hydrochloride, melting point 246° - 248°;

N-(4-propylsulphonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-isopropylsulphonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-butylsulphonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-isobutylsulphonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-hexylsulphonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-allylsulphonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-methallysulphonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-crotylsulphonylaminophenyl)-N',N'-dimethyl-acetamidine;

N-(4-cyclopropylsulphonylaminophenyl)-N',N'-dimethylacetamidine;

N-(4-cyclobutylsulphonylaminophenyl)-N',N'-dimethylacetamidine;

N-(4-cyclopentylsulphonylaminophenyl)-N',N'-dimethylacetamidine;

N-(4-cyclohexylsulphonylaminophenyl)-N',N'-dimethylacetamidine;

N-(4-cycloheptylsulphonylaminophenyl)-N',N'-dimethylacetamidine; and

N-(4-dodecylsulphonylaminophenyl)-N',N'-dimethylacetamidine.

EXAMPLE 8 ##STR25##

13.6 g of chloroformic acid ethyl ester are added dropwise at 20° to16.8 g of N-(4-aminophenyl)-N-methyl-N-methoxy-acetamidine in 200 ml ofethanol, the mixture is heated for one hour under reflux and evaporatedin vacuo, and after recrystallisation from ethanol/ethyl acetate 22.1 gof N-(4-carbethoxyaminophenyl)-N'-methyl-N'-methoxy-acetamidinehydrochloride are obtained.

The N-(4-aminophenyl)-N'-methyl-N'-methoxyacetamidine used as thestarting material is obtained in the following manner;p-nitroacetanilide is converted by means of phosphorus pentachlorideinto p-nitrophenyl-acetimide chloride, boiling point ₀.5 130° and thisis reacted with N,O-dimethylhydroxylamine to giveN-(4-aminophenyl)-N'-methyl-N'-methoxy-acetamidine, boiling point ₀.1150°, which is catalytically reduced toN-4-(aminophenyl)-N'-methyl-N'-methoxy acetamidine, boiling point ₀.1154°-156°.

The following compounds are obtainable by processes analogous to thatdesired in Example 8:

N-(4-carbomethoxyaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-carbobutoxyaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-propionaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-butyrylaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-methylsulphonylaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-ethylsulphonylaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-benzoylaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-phenylacetylaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-(4-methoxyacetylaminophenyl)-N'-methyl-N'-methoxy-acetamidine;

N-[4-furylcarbonyl-(2)-aminophenyl]-N'-methyl-N'-methoxy-acetamidine;

N[4(4-chlorobenzoylamino)phenyl]-N'-methyl-N'-methoxy-acetamidine;

N'[4-(3-methylbenzoylamino)phenyl]-N'-methyl-N'-methoxy-acetamidine;

N-[4-(2-pyridylcarbonylamino)phenyl]-N'-methyl-N'-methoxy-acetamidine;

N-[4-(4-pyridylcarbonylamino)phenyl]-N'-methyl-N'-methoxy-acetamidine;

N-[4-(5-methylisoxyzolycarbonyl-[3]-amino)phenyl]-N'-methyl-N'-methoxy-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-ethyl-N'-methoxy-acetamidine;

N-(4-acetaminophenyl)-N'-ethyl-N'-methoxy-acetamidine;

N-(4-methylsulphonylaminophenyl)-N'-ethyl-N'-methoxyacetamidine;

N-(4-ethylsulphonylaminophenyl)-N'-ethyl-N'-methoxyacetamidine;

N-(4-carbethoxyaminophenyl)-N'-ethyl-N'-ethoxy-acetamidine; and

N-(4-acetaminophenyl)-N'-ethyl-N'-ethoxy-acetamidine.

EXAMPLE 9 ##STR26##

14.05 g of benzoyl chloride are added dropwise, at 20°, to 17.7 g ofN-(4-aminophenyl)-N',N'-dimethyl-acetamidine in 150 ml of ethanol, andthe mixture is heated for one hour under reflux. After cooling, theN-(4-benzoylaminophenyl)-N',N'-dimethyl-acetamidine hydrochloride whichhas separated out is filtered off; after recrystallisation from ethanolit has a melting point of 273°-274°; yield: 24.4 g. A further 3.5 g canbe obtained from the mother liquor.

The following are obtained by analogous processes:

N[4-(4-chlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-chlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-chlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-methylbenzoylamino)-phenyl]N',N'-dimethylacetamidine;

N-[4-(3-methylbenzoylamino)-N',N'-dimethylacetamidine;

N-[4-(2-methylbenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(2,6-dichlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-nitrobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-nitro-2-chlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-bromobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(2,4-dichlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(2,3-dichlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(3,4-dichlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(2,3,6-trichlorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-fluorobenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-trifluoromethylbenzoylamino)-phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-chloro-6-acetyloxybenzoylamino)-phenyl]-N',N'-dimethylacetamidine,hydrochloride, melting point 292°-295°;

N-[4-(4-methoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;N-[4-(3-methoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-methoxybenzolamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-chloro-6-methoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-chloro-4-methoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2,3-dimethoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-carbethoxyamino-4-methoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-acetylamino-methoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-butoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-(4-ethoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3,4,5-trimethoxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-methylsulphonylbenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-methylsulphonylbenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3,4-dimethylbenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-methylsulphonylaminobenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-(4-(phenoxyacetylaminophenyl)-N',N'-dimethylacetamidine,hydrochloride, melting point 256°-257° (decomposition);

N-(4-(2-phenoxypropionylaminophenyl)-N',N'-dimethylacetamidine;

N-(4-(2-phenoxybutyrylaminophenyl)-N',N'-dimethylacetamidine;

N-[4-(methylphenoxy)-acetylaminophenyl]-N',N'-dimethylacetamidine;

N-[4-(2-methoxyphenoxy)-acetylaminophenyl]-N',N'-dimethylacetamidine;

N-[4-(2-isopropylphenoxy)-acetylaminophenyl]-N',N'-dimethylacetamidine;

N-[4-(3,4-dimethylphenoxy)-acetylaminophenyl]-N',N'-dimethylacetamidine;

N-[4-(3,5-dimethoxyphenoxy)-acetylaminophenyl]-N',N'-dimethylacetamidine;

N-[4-(2-chlorophenoxy)-acetylaminophenyl]-N',N'-dimethylacetamidine;

N-[4-(2-methyl-4-chlorophenoxy)acetylamino-phenyl]-N',N'-dimethylacetamidine;

N-[4-(2,4-dichlorophenoxyacetylamino-phenyl-]-N',N'-dimethylacetamidine;

N-[4-(2,5-dichlorophenoxy)acetylamino-phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-nitrophenoxy)acetaminophenyl]-N',N'-dimethylacetamidine;

N-(4-cinnamoylaminophenyl)-N',N'-dimethyl-acetamidine, hydrochloride,melting point 280°-285° (decomposition);

N-[4-(2,6-dichlorocinnamoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(1-naphthoylaminophenyl)]-N',N'-dimethylacetamidine;N-[4-(2-naphthoylaminophenyl)]-N',N'-dimethylacetamidine;

N-[4-(2-indenylcarbonylaminophenyl)]-N',N'-dimethylacetamidine;

N-[4-(1-indenylcarbonylaminophenyl)]-N',N'-dimethylacetamidine;

N-[4-(1-tetralylcarbonylaminophenyl)]-N',N'-dimethylacetamidine;

N-[4-(2-tetralylcarbonylaminophenyl)]-N',N'-dimethylacetamidine;

N-[4-(5-tetralylcarbonylaminophenyl)]-N',N'-dimethylacetamidine;

N-[4-(2-hydroxybenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-82-hydroxy-4-chlorobenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-hydroxy-3,5-dichlorobenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-acetoxy-3,5-dichlorobenzoylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-acetoxy-3-bromo-5-chlorobenzoylamino)phenyl]-N',N'-dimethylacetamidine;and

N-[4-(2-hydroxy-3,5,6-trichlorobenzoylamino)phenyl]-N',N'-dimethylacetamidine.

EXAMPLE 10 ##STR27##

A solution of 17.7 g of N-(4-aminophenyl)-N',N'-dimethyl-acetamidine in150 ml of benzene is heated with 50 ml of formic acid ethyl ester for 4hours under reflux. The mixture is evaporated; after distillation invacuo 18.7 g of N-(4-formylaminophenyl)-N',N'-dimethylacetamidine,boiling point ₀.1 185°-188°, are obtained; hydrochloride: melting point279°-281°.

EXAMPLE 11 ##STR28##

17.7 g of N-(4-aminophenyl)-N',N'-dimethylacetamidine in 100 ml ofacetic anhydride are heated for 4 hours under reflux, the mixture isevaporated, the residue is rendered alkaline with sodium hydroxidesolution, and the organic phase is taken up in chloroform/ether anddistilled in vacuo. 14.8 g ofN-(4-acetaminophenyl)-N',N'-dimethyl-acetamidine, melting point132°-134°, are obtained.

EXAMPLE 12

96 g of 4-acetaminoacetanilide in 300 ml of toluene are stirred with 76g of phosphorus oxychloride for 6 hours at 20°. A solution of 60 g ofdimethylamine in 200 ml of toluene is then added dropwise and themixture is heated overnight under reflux. After working up as describedin Example 1, 27 g of N-(4-acetaminophenyl)-N',N'-dimethylacetamidine,boiling point ₀.1 190°-200°, are obtained, melting at 131°-134° afterrecrystallisation.

EXAMPLE 13

A solution of 51.5 g of N,N-dimethylthioacetamide and 74 g ofp-aminoacetanilide in 500 ml of ethanol, with 185 g of mercury oxideadded, is vigorously stirred for 8 hours at 0° and then for 15 hours at80°. The precipitate is filtered off, the residue is distilled in vacuo,and 24.6 g of N-(4-acetaminophenyl)-N',N'-dimethyl-acetamidine, boilingpoint ₀.1 190°-200°, melting point 131°-134°, are obtained.

The same compound is also obtained from 4-acetaminothioacetanilide anddimethylamine in the presence of mercury oxide, by an analogous process.

EXAMPLE 14

50 ml of dimethylacetamide and 25 g of p-acetaminophenylisocyanate areheated under reflux until the evolution of CO₂ has ceased. The reactionproduct is distilled in vacuo, and 7.5 g ofN-(4-acetaminophenyl)-N',N'-dimethylacetamidine, boiling point ₀.1180°-200°, melting point 131°-134°, are obtained.

The same compound is also obtained by heating4-acetamino-phenylcarbamine acid chloride and with dimethylacetamide ordimethylthioacetamide.

EXAMPLE 15

98 g of 4-acetaminophenyl-acetiminoethyl-ether in a solution of 26 g ofdimethylamine in 100 ml of ethanol are heated for two days to 28° andthen for 6 hours in a sealed tube to 120°-130°. After evaporation anddistillation, 57 g of N-(4-acetaminophenyl)-N',N'-dimethylacetamidine,melting point 131°-134°, are obtained. Correspondingly, reaction of4-acetiminophenyl-acetiminoethyl-ether with ammonia yieldsN-(4-acetaminophenyl)-acetamidine. The same compound is also produced byreaction of 4-aminoacetanilide with acetiminoethyl-ether.

EXAMPLE 16 PRODUCTION OF A STARTING MATERIAL FOR USE IN A PROCESS OF THEINVENTION

140 g of p-amino-acetanilide and 36 g of acetonitrile in 400 ml ofcarbon disulphide are treated with 144 g of aluminium chloride over thecourse of 1 hour. The solvent is then distilled off, and the reactionmixture is heated for 4 hours to 150°-160°. Thereafter it is poured ontoa mixture of ice and water, the whole is filtered, the filtrate isrendered alkaline with saturated potassium carbonate solution, and theoil which has separated out is taken up in ether. After evaporating offthe solvent, 33 g of N-(4-acetaminophenyl)-acetamidine are obtained.Boiling point ₀.3 173°-176°.

EXAMPLE 17

11 g of sodium carbonate are added to a solution of 38.2 g ofN-(4-acetaminophenyl)-acetamidine as produced in Example 16 in 200 ml oftetrahydrofurane, and 57 g of methyl iodide are added dropwise. Themixture is heated overnight under reflux, inorganic constituents whichhave separated out are filtered off, the filtrate is concentrated invacuo, and the residue is taken up in water and rendered alkaline withsodium hydroxide solution. The separated base is taken up in a mixtureof ether/chloroform, which is evaporated, and is distilled. Afterrecrystallisation from ethyl acetate, 17.8 g ofN-(4-acetaminophenyl)-N',N'-dimethylacetamidine of melting point131°-134° are obtained.

The following are obtained by analogous processes:

N-(4-acetaminophenyl)-N'-allyl-acetamidine;

N-(4-acetaminophenyl)-N'-methallyl-acetamidine;

N-(4-acetaminophenyl)-N'-crotyl-acetamidine;

N-(4-propionylaminophenyl)-N'-allyl-acetamidine;

N-(4-propionylaminophenyl)-N'-methallyl-acetamidine;N-(4-carbethoxyaminophenyl)-N'-allyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-crotyl-acetamidine;

N-(4-methanesulphonylaminophenyl)-N'-allyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N',N'-diallyl-acetamidine;N-(4-acetaminophenyl)-N'-N'-diallyl-acetamidine;N-(4-propionaminophenyl)-N',N'-diallyl-acetamidine;N-(4-methylsulhonylaminophenyl)-N',N'-diallyl-acetamidine; and

N-(4-acetaminophenyl)-N',N'-dicrotyl-acetamidine.

EXAMPLE 18

Following the method described in Example 17, alkylation ofN-(4-acetaminophenyl)-N'-methylacetamidine with allyl chloride in thepresence of potassium carbonate yieldsN-(4-acetaminophenyl)-N'-allyl-N'-methyl-acetamidine.

The following are obtained by proceeding analogously:N-(4-acetaminophenyl)-N'-methyl-N'-crotyl-acetamidine;N-(4-acetaminophenyl)-N'-methyl-N'-methallyl-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-propynyl-acetamidine;

N-(4-acetaminophenyl)-N'-methyl-N'-butynyl-(2)-acetamidine;

N-(4-propionaminophenyl)-N'-methyl-N'-allyl-acetamidine;

N-(4-propionaminophenyl)-N'-methyl-N'-crotyl-acetamidine;

N-(4-propionaminophenyl)-N'-ethyl-N'-allyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-methyl-N'-allyl-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-methyl-N-butynyl-(2)-acetamidine;

N-(4-carbethoxyaminophenyl)-N'-ethyl-N'-allyl-acetamidine;

N-(4-methylsulphonylaminophenyl)-N'-methyl-N'-allyl-acetamidine;

N-(4-methylsulphonylaminophenyl)-N'-methyl-N'-crotyl-acetamidine;

N-(4-methylsulphonylaminophenyl)-N'-methyl-N'-propynyl-acetamidine; and

N-(4-ethylsulphonylaminophenyl)-N'-methyl-N'-allyl-acetamidine;

EXAMPLE 19 ##STR29##

Following the method described in Example 9, 17.7 g ofN-(4-aminophenyl)-N',N'-dimethylacetamidine and 15.7 g of2-furanecarboxylic acid chloride in ethanol yield 27.7 g ofN-[4-(2-furylcarbonylamino)phenyl]-N',N'-dimethyl-acetamidinehydrochloride, melting point 270°-272°.

The following are obtained by analogous processes:

N-[4-(5-methylisoxazolylcarbonyl-[3]-amino)phenyl]-N',N'-dimethylacetamidine,hydrochloride, melting point 308°-309°, decomposition;

N-[4-(2-pyridylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-pyridylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-pyridylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-thienylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-furfurylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-indolylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-thianaphthylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-indolylacetylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-quinolylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-phenothiazinylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(2-thienylacetylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(3-pyrazolylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-(4-methyl-3-pyrazolylcarbonylamino)phenyl]-N',N'-dimethyl-acetamidine;

N-[4-(2-imidazolylcarbonylamino)phenyl]-N',N'-dimethylacetamidine;

N-[4-pyrazinylcarbonyl-aminophenyl]-N',N'-dimethylacetamidine;

N-[4-(4-pyrimidinylcarbonylamino)phenyl]-N',N'-dimethylacetamidine; and

N-[4-(5-thiazolylcarbonylamino)phenyl-N',N'-dimethylacetamidine.

As already mentioned, the new aminophenylamidines and salts are suitablefor combating parasites, especially helminths.

It is distinctyl surprising and unforeseeable that a high anthelminticactivity should arise as a result of the introduction of an acylamino orof a sulphonylamino group into the phenyl nucleus of theN-phenylacetamidines. Furthermore, the new compounds have asubstantially better action than other known anthelmintics having thesame type of action, such as, for example, bephenium hydroxynaphthoates,phenylene-1,4-diisothiocyanate, perchloroethylene, thiabendazole andparbendazole. Particular attention is drawn to the fact that excellentresults are achieved with a single dose.

The provision by the invention of the new compounds available extendssubstantially the range of available medicines.

In particular, the compounds manufactured according to the invention forexample display a surprisingly good and broad action against thefollowing helminths (nematodes and cestodes):

I. nematodes

1. Ancylostoma canium, Uncinaria stenocephala and Bunostromuntrigonocephalum (hookworms) from the family of the Ancylostomatidae;

2. Haemonchus contortus, Trichostrongylus colubriformis, Cooperiapunctata, Ostertagia circumcincta, Nippostrongylus musis andNematospiroides dubius (worms of the stomach and of the small intestine)from the family of the Trichostrongylidae;

3. Oesophagostomum columbianum and Chabertia ovina (worms of the largeintestine) from the family of the Stronglylidae;

4. Strongyloides ratti (dwarf threadworms) from the family of theRhabditidae;

5. Toxocara canis, Toxascaris leonina and Ascaris suum larvae(coilworms) from the family of the Ascarididae.

6. Aspiculuris tetraptera (maggot worms) from the family of theOxyuridae;

7. Heterakis spumosa from the family of the Heterakidae.

Ii. cestodes

1. Hymenolepis nana and Hymenolepis microstoma (tapeworms) from thesuper-family of the Taenioidea.

The action was tested in animal experiments, by oral and parenteraladministration to test animals severely infected with parasites. Thedoses used were tolerated very well by the test animals. Even at 10 to100 times the therapeutically necessary dose, the test animals survivedthe treatments.

The unexpected superiority of the compounds according to the inventionover known compounds, as well as the excellent action against amultiplicity of parasites, is shown by the Examples A to G (Tables 1-7).

EXAMPLE A

Hookworm test/dog

Dogs experimentally infected with Ancylostome canium were treated afterthe end of the pre-patent period of the parasites.

The amount of active compound was administered orally as the pure activecompound or as a 10% strength solution in lactic acid, in gelatinecapsules.

The degree of action was determined by counting the worms expelled afterthe treatment and the worms remaining in the test animal, afterdissection, and calculating the percentage of worms expelled.

The active compounds tested, doses used and action are summarised inTable 1 below.

                                      Table 1                                     __________________________________________________________________________    Hookworm test/dog                                                                                                 Dose                                                                              Action                                Active compounds                    mg/kg                                                                             in %                                  __________________________________________________________________________    known compounds:                                                               ##STR30##                      (30)                                                                              50  0                                      ##STR31##                      (31)                                                                              25  0                                      ##STR32##                      (32)                                                                              300 82                                     ##STR33##                      (33)                                                                              50  51                                     ##STR34##                      *)  60  46                                     ##STR35##                      (34)                                                                              100 65                                     ##STR36##                      **) 100 200                                                                           77 93                                  *) Literature:                                                                Rawes, D.A. (1961): The Activity of Bephenium Hydroxynaphthoate against       Hookworms in the Dog. Vet. Rec. 73 (16), 390-392                              **) Literature:                                                               Theodorides, V.J. and M. Laderman (1968): Parbendazole in the Treatment o     Intestinal Nematodes of Dogs and Monkeys. Vet. Med. 63 (10), 985.             ##STR37##                      (36)                                                                              100 0                                     compounds according to the invention:                                          ##STR38##                      (19)                                                                              5 10 25                                                                           88 85 100                              ##STR39##                      (37)                                                                              2.5 5.0  10.0                                                                     98 98  100                             ##STR40##                      (20)                                                                              5 10                                                                              60 95                                  ##STR41##                      (21)                                                                              5 10                                                                               64 100                                ##STR42##                      (38)                                                                              25  92                                     ##STR43##                      (39)                                                                              5 10 25                                                                           65 77 100                              ##STR44##                      (27)                                                                              10  84                                     ##STR45##                      (25)                                                                              25  80                                     ##STR46##                      (40)                                                                              10 25                                                                             47 100                                 ##STR47##                      (41)                                                                              5   76                                     ##STR48##                      (42)                                                                              10  82                                     ##STR49##                      (43)                                                                              10  63                                     ##STR50##                      (44)                                                                              5   100                                    ##STR51##                      (45)                                                                              10  100                                    ##STR52##                      (29)                                                                              25  98                                     ##STR53##                      (46)                                                                              10  100                                    ##STR54##                      (47)                                                                              10  96                                    __________________________________________________________________________

EXAMPLE B

Hookworm test/dog

Dogs experimentally infected with Uncinaria stenocephala were treatedafter the end of the pre-patent period of the parasites.

The amount of active compound was administered orally as the pure activecompound or as a 10% strength solution in lactic acid, in gelatinecapsules.

The degree of action was determined by counting the worms expelled aftethe treatment and the worms remaining in the test animal, afterdissection, and calculating the percentage of worms expelled.

The active compounds tested, doses used and action are summarised inTable 2 below.

                                      Table 2                                     __________________________________________________________________________    Hookworm test/dog                                                                                        Dose                                                                              Action                                         Active compounds           mg/kg                                                                             in %                                           __________________________________________________________________________     ##STR55##             (19)                                                                              10  5                                                                             92 92                                           ##STR56##             (48)                                                                              5  2.5                                                                            99 42                                           ##STR57##             (49)                                                                              10  89                                             __________________________________________________________________________

EXAMPLE C

Hookworm test/dog

Dogs experimentally infected with Ancylostoma caninum were treated afterthe end of the pre-patent period of the parasites.

The amount of active compound was administered subcutaneously as a 1%strength solution in distilled water.

The degree of action was determined by counting the worms expelled afterthe treatment and the worms remaining in the test animal, afterdissection, and calculating the percentage of worms expelled.

The active compound tested, dose used and action are summarised in Table3 below.

                                      Table 3:                                    __________________________________________________________________________    Hookworm test/dog                                                                                          Dose                                                                              Action                                       Active compound              mg/kg                                                                             in %                                         __________________________________________________________________________     ##STR58##                (50)                                                                             5   99                                           __________________________________________________________________________

EXAMPLE D

Hookworm test/sheep

Sheep experimentally infected with Bunostomum trigonocephalum weretreated after the end of the pre-patent period of the parasites.

The amount of active compound was administered orally as pure activecompound in gelatine capsules.

The degree of action is determined by counting the worms expelled afterthe treatment and the worms remaining in the test animals, afterdissection, and calculating the percentage of worms expelled.

The active compounds tested, doses used and action are summarised inTable 4 below.

                                      Table 4:                                    __________________________________________________________________________    Hookworm test/sheep                                                                                      Dose                                                                              Action                                         Active compound            mg/kg                                                                             in %                                           __________________________________________________________________________     ##STR59##                (19)                                                                             1.0 2.5 5.0                                                                       95 98 100                                     ##STR60##                (50)                                                                             1.0 5.0                                                                           92 98                                         ##STR61##                (51)                                                                             10  100                                          __________________________________________________________________________

EXAMPLE E

Stomach and intestine worm test/sheep

Sheep experimentally infected with Haemonchus contortus andTrichostrongylus colubriformis were treated after the end of thepre-patent period of the parasites.

The amount of active compound was administered orally as pure activecompound, in gelatine capsules.

The degree of action is determined by quantitatively counting the wormeggs excreted with the faeces before and after treatment.

Complete cessation of the excretion of eggs after treatment means thatthe means have been expelled or so damaged that they can no longerproduce eggs (effective dose).

The active compound tested and the minimum effective dose is shown inTable 5.

                                      Table 5:                                    __________________________________________________________________________    Stomach and intestine worm test/sheep                                                                        Minimum effective                              Active compound        Parasite                                                                              dose mg/kg                                     __________________________________________________________________________     ##STR62##             Haemonchus contortus Trichostr. colubriformis                                         10 25                                          __________________________________________________________________________

EXAMPLE F

Large-intestine worm test/sheep

Sheep experimentally infected with Oesophagostomum columbianum weretreated after the end of the pre-patent period of the parasites.

The amount of active compound was administered orally as pure activecompound in gelatine capsules.

The degree of action is determined by counting the worms expelled afterthe treatment and the worms remaining in the test animals, afterdissection, and calculating the percentage of worms expelled.

The active compounds tested, doses used and action are shown in Table 6below.

                                      Table 6:                                    __________________________________________________________________________    Large-intestine worm test/sheep                                                                            Dose                                                                              Action                                       Active compounds             mg/kg                                                                             in %                                         __________________________________________________________________________     ##STR63##                (19)                                                                             1.0 5.0 10.0                                                                      65 100 100                                    ##STR64##                (50)                                                                             1.0 76                                           __________________________________________________________________________

EXAMPLE G

Coilworm test/dog

Dogs naturally infected with Toxocara canis and Toxascaris leonina weretreated orally.

The amount of active compound was administered orally as pure activecompound or as a 10% strength solution in lactic acid, in gelatinecapsules.

The degree of action is determined by counting the worms expelled afterthe treatment and the worms remaining in the test animals, afterdissection, and calculating the percentage of worms expelled.

The active compounds tested, doses used and action are summarised inTable 7 below.

                                      Table 7:                                    __________________________________________________________________________    Coilworm test/dog                                                                                                      Dose                                                                              Action                           Active compounds                   Parasite                                                                            mg/kg                                                                             in %                             __________________________________________________________________________     ##STR65##                      (19)                                                                             Toxocara                                                                            10  86                                ##STR66##                      (50)                                                                             Toxocara Toxascaris                                                                 2.5 5.0                                                                           100 83                            ##STR67##                      (20)                                                                             Toxocara                                                                            5 25                                                                              100 100                           ##STR68##                      (52)                                                                             Toxascaris                                                                          10  75                                ##STR69##                      (27)                                                                             Toxascaris                                                                          25  98                                ##STR70##                      (53)                                                                             Toxocara                                                                            25  100                               ##STR71##                      (41)                                                                             Toxocara                                                                            10  100                               ##STR72##                      (42)                                                                             Toxocara Toxascaris                                                                 10 5                                                                              100 75                            ##STR73##                      (54)                                                                             Toxocara                                                                            25  100                               ##STR74##                      (27)                                                                             Toxascaris                                                                          25  98                                ##STR75##                      (44)                                                                             Toxocara                                                                            25  100                               ##STR76##                      (46)                                                                             Toxocara                                                                            10  100                               ##STR77##                      (21)                                                                             Toxocara                                                                            10  83                               __________________________________________________________________________

In general it has proved advantageous to administer amounts of about 0.1to about 50 mg of the new compounds per kg of body weight per day inorder to achieve effective results.

Nevertheless, it may at times be necessary to deviate from the amountsmentioned, and in particular to do so as a function of the body weightof the test animal or of the nature of the method of administration, butalso because of the variety of animal and its individual behaviourtowards the medicament or because of the nature of the formulation ofthe latter and the point in time, or interval, at which it isadministered. Thus, it may in some cases suffice to use less than theabovementioned minimum amount, whilst in other cases the upper limitmentioned must be exceeded. Where major amounts are administered, it maybe advisable to divide these into several individual administrationsover the course of a day. The same dosage range is envisaged foradministration in human medicine and in veterinary medicine. The generalsense of the other comments made above also applies.

As stated above, the invention relates to the pharmaceutical use,including the veterinary use, of the new aminophenylamidines and theirnon-toxic salts.

Accordingly, the present invention provides a pharmaceutical compositioncontaining as an active ingredient at least one of the newaminophenylamidines of the general formula (1) given above, or anon-toxic salt thereof, in admixture with a pharmaceutically acceptablesolid or liquid diluent or carrier as hereinafter defined.

In the present specification the expression "pharmaceutically acceptablediluent or carrier" means a non-toxic substance that when mixed with theactive ingredient or ingredients renders it suitable for administration.The expression preferably excludes water and low-molecular weightorganic solvents commonly used in chemical synthesis, except in thepresence of other pharmaceutically necessary ingredients such as saltsin correct quantities to render the composition isotonic, buffers,surfactants, colouring and flavouring agents, and preservatives.Examples of suitable solid and liquid diluents and carriers are thefollowing: water containing buffering agents and/or rendered isotonic bythe addition of glucose or salts; non-toxic organic solvents; such asparaffins, (for example petroleum fractions); vegetable oils (forexample groundnut/sesame oil); alcohols, (for example ethyl alcohol orglycerol); glycols (for example propylene glycol or polyethyleneglycol); natural ground rock (for example kaolins, aluminas, talc orchalk); synthetic rock powders (for example highly disperse silica orsilicates); and sugars (for example unrefined sugar, lactose andglucose).

Examples of pharmaceutical compositions according to the invention areointments, pastes, creams, sprays, lotions, aqueous suspensions,elixirs, syrups, granules and powders, either free-flowing or compressedinto tablets.

The compounds and pharmaceutically acceptable salts of the presentinvention may be administered perorally.

One group of preferred pharmaceutical compositions of the invention aretherefore those adapted for oral administration. The diluents andcarriers used are preferably therefore those that adapt the activeingredient or ingredients for oral administration. Examples of suchdiluents and carriers are solid vehicles, excipients and lubricants suchas glucose, lactose and sucrose, corn and potato starch, sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate, powderedgun tragacanth, gelatin, alginic acid, agar, stearic acid, sodium,calcium and magnesium stearates, sodium lauryl sulphate,polyvinyl-pyrollidone, sodium citrate, calcium carbonate, and dicalciumphosphate.

The pharmaceutical compositions of the invention may also contain othernon-toxic adjuvants and modifiers such as dyes, surfactants for example,emulsifiers, such as non-ionic and anionic emulsifiers (for examplepolyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers,alkylsulphonates and arylsulphonates), and dispersing agents (forexample lignin, sulphite waste lyes, methylcellulose, starch andpolyvinylpyrrolidone), perfumes, flavouring agents, preservatives andbiocides.

The compounds and pharmaceutically acceptable salts of the invention mayalso be administered parenterally, in particular, subcutaneously. Agroup of preferred pharmaceutical compositions of the invention aretherefore those adapted for parenteral injection. The diluents andcarriers used here are therefore preferably those that adapt the activeingredient for parenteral adminisration. Examples of such diluents andcarriers are solvents and suspending diluents such as water andwater-miscible organic solvents, in particular sesame oil, groundnutoil, aqueous propylene glycol, and N,N'-dimethyl formamide. Examples ofpharmaceutical compositions of the invention are sterile isotonic salineaqueous solutions of the active ingredients, which may be buffered witha pharmaceutically acceptable buffer and are preferably pyrogen-free.0.1 The pharmaceutical compositions of the invention preferably contain0.1 to 90 wt.% of a new aminophenylamidine of the invention or anon-toxic salt thereof.

The present invention also provides medicaments in dosage unit form ashereinafter defined comprising as an active ingredient at least oneaminophenylamidine of general formula (1) given above or a non-toxicsalt thereof, either alone or in admixture with a pharmaceuticallyacceptable solid or liquid diluent or carrier. In this case the diluentor carrier is preferably as defined above but can also be water oranother common solvent.

The expression "medicament in dosage unit form" as used in the presentspecification means a medicament in the form of discrete portions eachcontaining a unit dose or a multiple or sub-multiple of a unit dose ofthe active ingredient(s); for example, one, two, three, or four unitdoses or a half, a third or a quarter of a unit dose. A "unit dose" isthe amount of the active ingredient(s) to be administered on oneoccasion and will usually be a daily dose, or for example a half, athird, or a quarter of a daily dose depending on whether the medicamentis to be administered once or, for example, twice, three times, or fourtimes a day.

The discrete portions constituting the medicament in dosage unit formcan include a protective envelope. The active ingredient can beundiluted and contained in such an envelope, or can be mixed with apharmaceutically acceptable solid or liquid diluent or carrier asdefined above. Such portions can for example be in monolithic coherentform, such as tablets, lozenges, pills, suppositories, or dragees; inwrapped or concealed form, the active ingredients being within aprotective envelope, such as wrapped powders, cachets, sachets,capsules, or ampoules; or in the form of a sterile solution suitable forparenteral injection, such as ampoules of buffered, isotonic, sterile,pyrogen-free aqueous solution; or in any other form known in the art.

As stated above, it is preferred to administer the newaminophenylamidines of general formula (1) or their salts perorally.Preferred medicaments in dosage unit form according to the invention aretherefore those adapted for oral administration, such as tablets, pills,dragees, capsules, and cachets, as well as wrapped powders containingthe active ingredients in powdered form with a powdered diluent orcarrier for suspension in water before being taken.

As stated above the new aminophenylcycloamidines can also beadministered parenterally. Preferred medicaments in dosage unit formaccording to the invention are therefore those adapted for parenteralinjection, such as ampoules containing a measured quantity of a sterileisotonic saline injectable aqueous solution of the new activeingredient, which may be buffered with a pharmaceutically acceptablebuffer and are preferably free of pyrogens.

The preferred unit dose for administration in human medicine of themedicaments of the invention is 5-4500 mg. more preferably 50-2250 mg ofactive ingredient.

The invention further provides a method of combating parasitic infectionin an animal which comprises administering to the animal (preferablyparenterally or perorally) an aminophenylamidine of general formula (1)or a non-toxic salt thereof, or a pharmaceutical composition accordingto the invention, or a medicament in dosage unit form according to theinvention.

What we claim is:
 1. A compound selected from the group consisting of anaminophenylamidine and the physiologically acceptable acid additionsalts thereof, said aminophenylamidine having the formula: ##STR78##wherein R is alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 5 carbonatoms or cycloalkyl of 3 to 7 carbon atoms;R³ is hydrogen, chloro,fluoro, bromo, cyano, trifluoromethyl, alkyl of up to 4 carbon atoms,alkoxy of up to 4 carbon atoms and alkenyl of up to 4 carbon atoms; R⁴is an aliphatic substituent of up to 4 carbon atoms selected from thegroup consisting of alkyl, alkenyl, alkynyl and alkoxy; R⁵ is analiphatic substituent of up to 4 carbon atoms selected from the groupconsisting of alkyl or alkenyl, or cycloalkyl of 3 to 7 carbon atoms,and R⁶ is selected from the group consisting of phenyl, phenoxy,naphthyl, tetralyl, benzyl, phenethyl, benzyloxy, phenylethoxy,phenoxymethyl and phenoxymethoxy, unsubstituted or substituted with 1 to3 members selected from the group consisting of nitro, trifluoromethyl,hydroxy, cyano, chloro, fluoro, bromo, methyl, methoxy, carbethoxy,methylsulfonyl, acetylamino, or acetyloxy.
 2. The compound according toclaim 1 which is N-(4-benzoylaminophenyl)-N',N'-dimethylacetamidine. 3.The compound according to claim 1 which isN-(4-(phenoxyacetylaminophenyl)-N',N'-dimethylacetamidine.
 4. Thecompound according to claim 1 which isN-(4-carbobenzoxyaminophenyl)-N',N'-dimethyl-acetamidine.
 5. Thecompound according to claim 1 which isN-(4-carbophenethyloxyaminophenyl)-N',N'-dimethyl-acetamidine.
 6. Thecompound according to claim 1 which isN-(4-phenylacetylaminophenyl)-N',N'-dimethyl-acetamidine.
 7. Thecompound according to claim 1 which isN-(4-phenethylcarbonylaminophenyl)-N' ,N'-dimethyl-acetamidine.
 8. Thecompound according to claim 1 which is N-(4-benzoylaminophenyl)-N'-methyl-N'-methoxy-acetamidine.
 9. The compound according to claim 1which is N-(4-phenylacetylaminophenyl)-N-methyl-N'-methoxyacetamidine.10. The compound according to claim 1 which isN-[4-(3-chloro-6-acetyloxybenzoylamino)-phenyl]-N',N'-dimethyl-acetamidine.